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ATM aberrations in chronic lymphocytic leukemia: del(11q) rather than ATM mutations is an adverse-prognostic biomarker
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain.;Ctr Investigaci Biomed Red Canc CIBERONC, Madrid, Spain..
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2025 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 39, no 7, p. 1650-1660Article in journal (Refereed) Published
Abstract [en]

Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

Place, publisher, year, edition, pages
Springer Nature, 2025. Vol. 39, no 7, p. 1650-1660
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Hematology Neurosciences Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-569106DOI: 10.1038/s41375-025-02615-5ISI: 001473957800001PubMedID: 40275070Scopus ID: 2-s2.0-105003449208OAI: oai:DiVA.org:uu-569106DiVA, id: diva2:2005766
Funder
EU, Horizon 2020, 65269705EU, Horizon 2020, NV21-08-00237Swedish Cancer Society, 22 2448 PjSwedish Research Council, 2020-01750Region Stockholm, ALF/FoUI-962423Available from: 2025-10-10 Created: 2025-10-10 Last updated: 2025-10-10Bibliographically approved

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Mattsson, MattiasBaliakas, Panagiotis

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